Targeting the BBB to treat CNS inflammation

靶向 BBB 治疗中枢神经系统炎症

基本信息

  • 批准号:
    8826187
  • 负责人:
  • 金额:
    $ 28.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-25 至
  • 项目状态:
    未结题

项目摘要

Project 2 will determine how targeting molecules that regulate permeability and polarity at central nervous system (CNS) endothelial barriers impacts neuroinflammation, as assessed via novel neuroimaging modalities with murine models of multiple sclerosis (MS). We have shown that endothelium in MS lesions exhibits altered polarity, displaying the abluminal chemokine CXCL12 aberrantly along luminal surfaces. Abluminal CXCL12 normally serves to limit leukocyte entry whereas luminal expression of CXCL12 is associated with increased activation of its signaling receptor CXCR4 on infiltrating leukocytes. We showed that the scavenging CXCL12 receptor, CXCR7 (also expressed by CNS endothelium), is a critical regulator of leukocyte entry via internalization of CXCL12 from abluminal surfaces. In preliminary studies, we have also found that sphingosine 1-phosphate (S1P) signaling via S1P2 disturbs abluminal expression of CXCL12, which then disrupts immune privilege. Thus, mice with targeted deletion of S1P2 or administered a specific antagonist, JTE-013, show reduced migration of leukocytes into the CNS parenchyma during EAE. We hypothesize that alterations in membrane polarity of CXCL12 at CNS endothelial barriers promote leukocyte capture and migration into the CNS, contributing to the establishment of disease cycles in relapsing-remitting forms of CNS autoimmunity. We have identified several molecules that regulate this process, leading to reversal of apicobasal expression of the localizing cue, CXCL12. In this proposal, we will examine the roles of CXCR7 and S1P2 in lymphocyte trafficking and inflammation in CNS autoimmune disease using novel imaging modalities including two-photon intravital microscopy and longitudinally using Diffusion Basis Spectrum Imaging (DBSI), which distinguishes and quantitates cellularity and edema in live mice (see Project 1) and examination of autopsied human MS patient and control CNS tissues. We expect DBSI to be more sensitive than Gd enhancement to inflammation, including in the setting of less profound blood-brain barrier alterations. To determine the relationships between endothelial and immune cell (Th1 versus Th17) interactions and loss of BBB integrity, we will directly compare results utilizing intravital imaging to DBSI and Gd enhancement in the same animals. To address mechanisms by which endothelial cell polarity and localizing cues are induced by interactions with inflammatory cells, we will utilize in vitro and in situ approaches with human tissues. Thus, Aim 1 will determine whether CXCR7-mediated internalization of CXCL12 requires infiltration with Th1 versus Th17 cells during EAE. Aim 2 will determine whether S1P2- mediated reversal of endothelial cell polarity leads to increased T cell capture and entry during EAE, and Aim 3 will examine the relationship between CXCR7 and S1PR2 activation and T cell migration at the BBB in MS. The experimental design of Project 2 will define how DBSI determined cellularity and edema changes responding to various degrees of BBB abnormality and cell infiltration in EAE mice.
项目2将确定如何靶向调节渗透率和极性的分子

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Robyn S Klein其他文献

West Nile virus: crossing the blood-brain barrier
西尼罗河病毒:穿越血脑屏障
  • DOI:
    10.1038/nm1204-1294
  • 发表时间:
    2004-12-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Michael S Diamond;Robyn S Klein
  • 通讯作者:
    Robyn S Klein
Infectious diseases research in 2024: insights into dementia
2024 年传染病研究:对痴呆症的见解
  • DOI:
    10.1016/s1474-4422(24)00497-6
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
    45.500
  • 作者:
    Robyn S Klein
  • 通讯作者:
    Robyn S Klein

Robyn S Klein的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Robyn S Klein', 18)}}的其他基金

2023 Neuroimmune Communication in Health and Disease Gordon Research Conference and Gordon Research Seminar
2023健康与疾病中的神经免疫通讯戈登研究会议暨戈登研究研讨会
  • 批准号:
    10609280
  • 财政年份:
    2022
  • 资助金额:
    $ 28.31万
  • 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
  • 批准号:
    10397683
  • 财政年份:
    2021
  • 资助金额:
    $ 28.31万
  • 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
  • 批准号:
    10239672
  • 财政年份:
    2021
  • 资助金额:
    $ 28.31万
  • 项目类别:
Astrocyte innate immune mechanisms of post-viral cognitive dysfunction
病毒后认知功能障碍的星形胶质细胞先天免疫机制
  • 批准号:
    10115451
  • 财政年份:
    2020
  • 资助金额:
    $ 28.31万
  • 项目类别:
Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis
黄病毒脑炎病毒学控制和恢复的先天免疫机制
  • 批准号:
    10247164
  • 财政年份:
    2020
  • 资助金额:
    $ 28.31万
  • 项目类别:
NEUROPATHOGENESIS OF ZIKA VIRUS INFECTIONS
寨卡病毒感染的神经发病机制
  • 批准号:
    9762238
  • 财政年份:
    2018
  • 资助金额:
    $ 28.31万
  • 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
  • 批准号:
    9090530
  • 财政年份:
    2016
  • 资助金额:
    $ 28.31万
  • 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
  • 批准号:
    9204440
  • 财政年份:
    2016
  • 资助金额:
    $ 28.31万
  • 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
  • 批准号:
    9275040
  • 财政年份:
    2008
  • 资助金额:
    $ 28.31万
  • 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
  • 批准号:
    8741885
  • 财政年份:
    2008
  • 资助金额:
    $ 28.31万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 28.31万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了